Process for preparing ligands of ppardelta and the intermediate compounds for preparing the same

ABSTRACT

The present invention provides a process for preparing thiazole derivatives of formula (I), that activate the delta subtype of the human Peroxisome Proliferator Activated Receptor (hPPAR δ), and also provides compounds of formula (II), (IV), (X), (XI) and (XII), intermediate compounds for preparation of the above compounds of formula (I).

RELATED APPLICATIONS

The present application is a divisional application of U.S. applicationSer. No. 11/913,822, filed May 30, 2008, which is based on, and claimspriority from, PCT Application Number PCT/KR05/001341, filed May 7,2005, the contents of which are hereby incorporated by reference hereinin their entireties.

TECHNICAL FIELD

The present invention relates to a process for preparing thiazolederivative of formula (I), that activates the delta subtype of the humanPeroxisome Proliferator Activated Receptor (hPPAR δ), and also relatesto the compounds of formula (II), (IV), (X), (XI) and (XII),intermediate compounds for preparation of the above compound of formula(I).

BACKGROUND ART

Especially,2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-yl}methyl)sulfanyl]phenoxy}aceticacid (hereinafter, called to “GW501516”) among thiazole derivatives offormula (I) showed an excellent effect to treatment of obesity in animalmodels (Cell 2003, 113, 159), and proved effectiveness in cardiovasculardisease by increasing high density lipoprotein (HDL) and decreasing lowdensity lipoprotein (LDL) effectively in the animal experiment (Proc.Natl. Acad. USA 2001, 98, 5306) and in clinical trial. And the processfor preparation of the said substance has been disclosed in PCTpublication WO 01/00603A1, Bioorg. Med. Chem. Lett. 2003, 13, 1517 andJ. Chem. Org. 2003. 68. 9116, in which GW501516 (13) was prepared, asshown in the following scheme (1). Methyl(4-mercapto-3-methylphenoxy)acetate (7), synthesized from the startingmaterial, 4-hydroxy-3-methylacetophenone (1), via 6 steps, was coupledto 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)thiazole (11),which was prepared from 4-(trifluoromethyl)thiobenzamide (8) via 3steps, in the presence of excessive cesium carbonate to obtain themethyl ester (12) of GW501516, and then treating the ester with 1 Nlithium hydroxide to give GW501516.

As an alternative synthesis method of GW501516, it is disclosed, asillustrated in the following scheme (2), that the compound (13) ofGW501516 can be prepared by introducing ethyl acetate group to o-cresol(14), reacting the resulted compound (15) with sulfonyl chloride,reducing the resulted compound (16) with tin (Sn) under acidic conditionto form ethyl (4-mercapto-2-methyl phenoxy)acetate (17), reacting itwith 5-chloromethyl-4-methyl-2-(4-trifluoromethyl phenyl)thiazole (11)together with an excessive cesium carbonate to obtain the ethyl esterintermediate (18) of GW501516, and deprotecting the ester group of theintermediate compound with 1N lithium hydroxide.

As another alternative synthesis method of GW501516, it is disclosed, asillustrated in the following scheme (3), that the compound (13) ofGW501516 can be prepared by reacting o-cresol with sodium thiocynate inthe presence of bromine, reducing the resulted compound with lithiumaluminium hydride to form 4-mercapto-2-methylphenol (20), reacting itwith 5-chloromethyl-4-methyl-2-(4-trifluoromethyl phenyl)thiazole (11)and methylbromoacetate sequentially to obtain the ethyl esterintermediate (12) of GW501516, and deprotecting the ester group of theintermediate compound with 2 M lithium hydroxide.

DISCLOSURE OF THE INVENTION

Although the above compound (13) has known to be an excellent efficacyin the treatment of obesity in animal models and in the treatment ofdisease states associated with cholesterol metabolism in clinicaltrials, the manufacturing method thereof was not satisfactory, therebybeing not cost-effective. That is to say,

-   -   1) The manufacturing method of reaction scheme (1) consists of        12 steps, and the total yield thereof is as low as 2%. So, it is        not proper to be applied to the industry, due to its extreme low        production yield.    -   2) The manufacturing process according to the reaction        scheme (1) includes three refluxing steps at elevated        temperature for 16 hours, which takes long time to obtain the        final product.    -   3) Tin (Sn) powder used in reaction scheme (2) is very unstable        to the moisture, and moreover, it is a combustible metal,        thereby being very dangerous to adopt it in industrial scale.    -   4) An excessive tin (Sn) powder used in the reaction scheme (2)        may lead to pollution of the environment.    -   5) Bromine (Br₂) used in the reaction scheme (3) may lead to        pollution of environment.    -   6) A separated another step for reacting compound (II) with        compound (7), (17) or (20) in the reaction scheme (1), (2)        or (3) is required, and also an excess amount of cesium        carbonate, which is not common inorganic base, is used, and also        the reaction time is comparatively long.    -   7) The hydrolysis steps of methyl or ethyl ester using 1 N        lithium hydroxide in reaction scheme (1) or (2) requires a long        reaction time, about 16 hours, of which yield is as low as 60%.    -   8) Methyl or ethyl (4-mercapto-2-methylphenoxy)acetate (7), (17)        or 4-mercapto-2-methylphenol (20) obtained as an intermediate        compound in the reaction scheme (1), (2) or (3) is unstable, so        the respective compound can be easily changed to disulfides,        which results in lowering the total reaction yield.

Under the circumstance, the novel process for preparing the abovecompound with easiness and low cost has been demanded in the art.

In view of the above situation, the inventors of the present inventionhave conducted extensive studies on the novel processes for preparingcompounds of the following formula (I). As a result, the inventors havefound that the said compounds can be prepared in a high yield and highpurity by reacting compounds of formula (II) with alkyl halogen acetateof formula (III) to form compounds of formula (IV) and hydrolyzing theresulting compounds, as shown in the following reaction scheme.

wherein, R₁ represents a hydrogen atom, halogen atom or CF₃,

R₂ represents a hydrogen atom, fluorine atom, chlorine atom, —(C₁-C₄)alkyl, —O(C₁-C₄) alkyl, —S(C₁-C₄) alkyl or —N(C₁-C₄ alkyl)₂ group,

R₃ represents carboxlic protecting group having —(C₁-C₄) alkyl groupsuch as methyl, ethyl, propyl, isopropyl, butyl or tert-butyl group,

X represents a halogen atom,

m is an integer of 0 to 4,

n is an integer of 0 to 5.

An object of the present invention is to provide a process for preparingcompounds of formula (I) in a high yield in a short period, via unstableintermediate compounds without separation step in the reaction.

The present invention also provides a process for preparing compounds offormula (VI) for preparing compounds of formula (II), which comprises byreacting compounds of formula (V) with alkyl 2-chloroacetoacetate.

The present invention further provides a process for preparing compoundsof formula (VII) for preparing compounds of formula (II), whichcomprises by reducing the ester moiety of compounds of formula (VI).

The present invention further provides a process for preparing compoundsof formula (VIII) for preparing compounds of formula (II), whichcomprises by introducing a leaving group, which is reactive to alcohols,to compounds of formula (VII).

The present invention further provides a process for preparing compoundsof formula (X), which comprises by reacting compounds of formula (IX)with Grignard reagents.

The present invention further provides a process for preparing compoundsof formula (II), a starting material of the present invention, whichcomprises by reacting compounds of formula (X) with organometallicreagents and sulfur (S₈) to form compounds of formula (XI) and (XII)sequentially, and reacting them with compounds of formula (VIII) withouta specific organic or inorganic base.

The present invention further provides novel compounds of formula (II),(IV), (X), (XI) and (XII), each of which useful as intermediatecompounds for preparation of the final products of the presentinvention.

[wherein, R₁, R₂, R₃, n and m have the same definitions as describedabove]

X₁ represents a leaving group. A generally used leaving group ispreferred, such as a halogen atom, methanesulfonate (MsO—), andp-toluenesulfonate (TsO—). Here, a halogen atom means a fluorine atom,chlorine atom, bromine atom or iodine atom. Of these, a halogen atom ispreferred, with a chlorine atom, bromine atom and iodine atom beingparticularly preferred.

Example of the halogen atom represented by X₂ includes a fluorine atom,chlorine atom, bromine atom or iodine atom. Of these, a bromine atom andiodine atom are preferred.

X₃ represents a halogen atom forming Grignard reagents such as achlorine atom or bromine atom.

The compounds of the formula (V) and (IX), which are used for preparingthe starting material (II), are commercially available or can besynthesized easily by using known methods in the art.

BEST MODE FOR CARRYING OUT THE INVENTION

The process of the present invention will be described as set below.

[Step A] Preparation of Compounds of Formula (VI):

Compounds of formula (VI) can be prepared by reacting compounds offormula (V) with ethyl or methyl 2-chloroacetoacetate in a solvent.

Suitable solvents usable in this reaction include alcohols such asmethanol, ethanol, propanol, and butanol; and ethers such as diethylether, tetrahydrofuran, and 1,4-dioxane. Of these, ethanol ortetrahydrofuran is preferred as a solvent.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct the reaction at 25 to 150° C. for 6hours to 1 day, more preferably 60 to 120° C. within 16 hours.

[Step B] Preparation of Compounds of Formula (VII):

Compounds of formula (VII) can be prepared by reducing the ester moietyof compounds of formula (VI) in an anhydrous solvent.

As reducing agents, aluminum hydrides such as lithium aluminum hydride,and diisobutylaluminum hydride, and boron hydrides such as sodiumborohydride and lithium borohydride can be given. Among them, lithiumaluminum hydride and diisobutylaluminum hydride are preferred.

As anhydrous solvents usable in this reaction, diethyl ether,tetrahydrofuran, and dichloromethane can be given, with preferably,dichloromethane.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct the reaction at −100 to 60° C. for30 minutes to 6 hours, more preferably −78 to 25° C. within 2 hours.

[Step C] Preparation of Compounds of Formula (VIII):

Compounds of formula (VIII) can be prepared by subjecting halogenationreaction on compounds of formula (VII), or reacting compounds of formula(VII) with methanesulfonyl chloride or p-toluene sulfonyl chloride in asolvent.

Suitable solvents usable in this reaction include N,N-dimethylformamide,diethyl ether, tetrahydrofuran, tetrachloromethane, chloroform,dichloromethane, and pyridine. Of these, dichloromethane forhalogenation reaction, and pyridine for methanesulfonate orp-toluenesulfonate reaction respectively are preferred.

Suitable reagents for halogenation reaction to the alcohol moietyinclude triphenylphosphine (TPP) with N-chlorosuccinimide (NCS),triphenylphosphine with chlorine gas, triphenylphosphine withtetrachloromethane (CCl₄), phosphorus pentachloride (PCl₅),thionylchloride (SOCl₂), and methanesulfonyl chloride (MeSO₂Cl) forintroduction of chlorine atom; triphenylphosphine withN-bromosuccinimide (NBS), triphenylphosphine with bromine gas,triphenylphosphine with tetrabromomethane (CBr₄), phosphoruspentabromide (PBr₅), and thionyl bromide (SOBr₂) for introduction ofbromine atom; triphenylphosphine with N-iodosuccine imide (NIS),triphenylphosphine with solid iodine, and triphenylphosphine withtetraiodomethane (CI₄) for introduction of iodine atom. Alternatively,introduction of iodine atom can be carried out by substituting chloro-or bromocompounds of formula (VIII) with sodium iodide (NaI) in acetone,so-called halogen-iodine substitution method. Methanesulfonyloxy groupor p-toluenesulfonyloxy group can be introduced by a reaction withmethanesulfonyl chloride or p-toluene sulfonyl chloride in a pyridinesolvent. Of these, the preferred leaving group is chlorine or bromineatom, and the preferred reagent for this reaction is triphenylphosphinewith N-chlorosuccinimide or N-bromosuccinimide.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct this reaction at −10 to 40° C. for30 minutes to 1 day, more preferably 10 to 25° C. within 2 hours.

[Step D] Preparation of Compounds of Formula (II) from Compounds ofFormula (VIII) and (XII):

Compounds of formula (II) can be prepared by protecting phenol groups ofcompounds of formula (IX) with Grignard reagents, reacting them withorganometallic reagents and sulfur sequentially, and then reacting theresulted compounds with compounds of formula (VIII). This reactioncomprises four step reactions, which are conducted at once.

[Step D-1] Preparation of Compounds of Formula (X) from Compounds ofFormula (IX):

Suitable anhydrous solvents usable in this reaction include diethylether, tetrahydrofuran, hexane, and heptane. These solvents may be usedeither singly or in combination of two or more. Of these, a solvent incombination of diethyl ether and tetrahydrofuran is preferred.

Suitable Grignard reagents usable in this reaction include methyl-,ethyl-, n-propyl-, isopropyl-, n-butyl- and isobutyl-magnesium chloride(R₂MgCl) or bromide (R₂MgBr). Of these, isopropyl magnesium chloride orbromide is preferred.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct this reaction at 20 to 40° C. for 10to 60 minutes, more preferably at 0 to 25° C. for 10 to 30 minutes.

[Step D-2] Preparation of Compounds of Formula (XI) from Compounds ofFormula (X) and [Step D-3] Preparation of Compounds of Formula (XII)from Compounds of Formula (XI):

As suitable organometallic reagents used for halogen-metal substitution,n-butyl lithium, sec-butyl lithium, and tert-butyl lithium can be used.Of these, tert-butyl lithium is preferred.

Suitable sulfur usable in this reaction is fine sulfur powder and it ispreferred to dissolve sulfur in solvents and add it slowly.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct this reaction at −78 to 25° C., morepreferably in the step of halogen-metal substitution at −75° C. for 10to 30 minutes and in the step of sulfur introduction at −75° C., laterraising the reaction temperature up to 0° C. for 30 to 90 minutes.

[Step D-4] Preparation of Compounds of Formula (II) from Compounds ofFormula (VIII) and (XII):

Suitable halogen atoms of5-halogenmethyl-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole offormula (VIII) usable in this reaction include a chlorine atom, bromineatom, and iodine atom, preferably a chlorine atom.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct this reaction at −78 to 25° C. for10 to 120 minutes, more preferably at 0 to 10° C. for 10 to 60 minutes.

[Step E] Preparation of Compounds of Formula (IV).

Compounds of formula (IV) can be prepared by reacting compounds offormula (II) with alkyl halogen acetates of formula (III) in thepresence of a base in a solvent.

The alkyl halogen acetates are commercially available or can besynthesized by known methods in the art. The alkyl group and halogentherein include methyl, ethyl, tert-butyl and a chlorine atom, bromineatom, and iodine atom, respectively. The most preferred one among thealkyl halogen acetates is methyl (or ethyl) chloro (or bromo) acetate.

Suitable solvents usable in this reaction include N,N-dimethylformamide,N, N-dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile. Thesesolvents may be used either singly or in combination with 1 to 10%water. Of these, acetone and dimethyl sulfoxide including 5% water arepreferred.

There is no specific limitation to bases used regardless of basicity,inasmuch as the base does not affect the reaction. Suitable basesinclude alkali metal hydrides such as sodium hydride, lithium hydride,potassium hydride; alkali metal hydroxide such as sodium hydroxide,potassium hydroxide and alkali metal carbonate such as lithiumcarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate,and potassium bicarbonate. Of these, alkali metal hydride or alkalimetal carbonate is preferred, with potassium carbonate beingparticularly preferred.

Although there is no specific limitation to the reaction temperaturewithin the boiling point of the solvent to be used, the reaction at arelatively high temperature is not preferred. It is preferred to conductthis reaction at 0 to 60° C. The reaction time depends on the reactiontemperature, however, it is preferred to conduct this reaction for 30minutes to 1 day, more preferably for 30 to 90 minutes.

[Step F] Preparation of Compounds of Formula (I).

Compounds of formula (I) can be prepared by subjecting hydrolysis of thecarboxylic ester of compounds of formula (IV) in the presence of awater-soluble inorganic base and alcohol solvent.

Suitable solvents usable in this reaction include methanol, ethanol, andwater miscible organic solvents.

As a base usable in this reaction, about 0.1 to 6 N aqueous solution ofalkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, orpotassium hydroxide, is used. Of these, 1 to 3 N sodium hydroxide ispreferred.

The reaction time and temperature depend on the solvent to be used.However, it is preferred to conduct this reaction at −10 to 80° C. for10 minutes to 3 hours, more preferably 0 to 25° C. for 30 minutes to 1hour.

Compounds of formula (I) obtained as above are ligands of the human PPARprotein, PPARδ.

EXAMPLES

The present invention will next be described in detail by way ofexamples, which should not be construed as limiting the invention.

Example 1 Preparation of methyl4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole-5-carboxylate [Step A]

4-(Trifluoromethyl)thiobenzamide (20.5 g, 0.1 mol) was dissolved intetrahydrofuran (300 ml) at room temperature, and then methyl2-chloroacetoacetate to (12.2 ml, 0.1 mol, 1.0 eq.) was added slowly forabout 20 minutes therein while stirring. After completion of addition,the mixture was stirred again at room temperature for 30 minutes, andthen the mixture was heated and refluxed at 75 to 80° C. for 12 hours.After completion of the reaction, the reaction mixture was cooled toroom temperature. Subsequently, 50% aqueous solution of sodium hydroxide(150 ml) was added and stirred for 20 minutes. The resultant organiclayer was separated by extraction with brine and ethyl acetate, anddried over magnesium sulfate. The solvent was evaporated under reducedpressure to thereby yield 28.8 g of the title compound (yield: 95.6%).

¹H-NMR (300 MHz, CDCl₃): 8.01 (d, 2H, J=8.4 Hz), 7.64 (d, 2H, J=8.3 Hz),3.84 (s, 3H), 2.73 (s, 3H).

Example 2 Preparation of[4-methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-yl]-methanol [Step B]

Methyl 4-methyl-2-[4-(trifluoromethyl)phenyl]]thiazole-5-carboxylate(20.0 g, 66.4 mmol) obtained from Example 1 was dissolved in anhydrousdichloromethane (500 ml) under nitrogen atmosphere, and the reactionmixture was cooled to −78° C. Diisobutyl aluminum hydride (DIBAL-H, 166ml, 1.0 M hexane solution, 2.5 eq.) was slowly added to the solution for30 minutes, and the mixture was reacted for another 30 minutes at thesame temperature. Subsequently, the temperature was raised to −10° C.and reacted for 30 minutes. After completion of the reaction, anexcessive diisobutyl aluminum hydride was removed by ethyl acetate. Theresultant residue was extracted by 10% sulfuric acid and ethyl acetate,followed by drying over magnesium sulfate. The resultant mixture wasevaporated under reduced pressure to thereby yield 17.5 g of the titlecompound (yield: 96.4%).

¹H-NMR (300 MHz, CDCl₃): 7.94 (d, 2H, J=8.1 Hz), 7.63 (d, 2H, J=8.2 Hz),4.80 (s, 2H), 2.93 (bs, 1H), 2.41 (s, 3H).

¹³C-NMR (78.5 MHz, CDCl₃): 164.6, 151.0, 137.0, 133.1, 132.0 (q, J=33Hz), 126.8, 126.3 (q, J=4 Hz), 122.5, 57.1, 15.4.

Example 3 Preparation of5-bromomethyl-4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole [Step C]

[4-Methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-yl]methanol (15.0 g,55.0 mmol) obtained from Example 2 was dissolved in anhydrousdichloromethane (300 ml), and then triphenylphosphine (TPP, 15.7 g, 60.0mmol, 1.1 eq.) and tetrabromomethane (20.0 g, 60.0 mmol, 1.1 eq.) wereadded to the mixture sequentially at room temperature. After stirringfor 1 hour, the solvent was evaporated from the reaction mixture underreduced pressure. Subsequently, the remained triphenylphosphine oxidewas precipitated by a mixed solvent of hexane and ethyl acetate(v/v=5/1), followed by filtration and evaporation under reduced pressureto thereby yield 17.2 g of the title compound (yield: 93%).

¹H-NMR (300 MHz, CDCl₃): 8.00 (d, 2H, J=8.1 Hz), 7.67 (d, 2H, J=8.2 Hz),4.72 (s, 2H), 2.47 (s, 3H).

¹³C-NMR (75.5 MHz, CDCl₃): 165.0, 153.8, 136.9, 132.4, 129.7 (q, J=33Hz), 127.0, 126.3 (q, J=4 Hz), 122.5, 23.8, 15.5.

Example 4 Preparation of5-bromomethyl-4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole [Step C]

[4-methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-yl]methanol (10.0 g,36.6 mmol) obtained from Example 2 was dissolved in anhydrousdichloromethane 300 ml, and then triphenylphosphine (TPP, 10.6 g, 40.3mmol, 1.1 eq.) and N-bromosuccinimide (7.17 g, 40.3 mmol, 1.1 eq.) wereadded to the mixture sequentially at room temperature. After stirringfor 1 hour, the solvent was evaporated from the reaction mixture underreduced pressure. Subsequently, the remained triphenylphosphine oxidewas precipitated by a mixed solvent of hexane and ethyl acetate(v/v=5/1), followed by filtration and evaporation under reduced pressureto thereby yield 11.1 g of the title compound (yield: 90.5%).

Example 5 Preparation of5-chloromethyl-4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole [Step C]

[4-Methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-yl]methanol (5.0 g,18.3 mmol) obtained from Example 2 was dissolved in tetrachloromethane(300 ml), and then triphenylphosphine (TPP, 6.3 g, 23.8 mmol, 1.3 eq.)was added and the mixture was stirred under reflux for 10 hours. Aftercompletion of the reaction, the temperature of the reactor was cooled toroom temperature, and a mixed solvent of hexane and ethyl acetate(v/v=5/1) was added thereto to precipitate the remainedtriphenylphosphine oxide, followed by filtration and evaporation underreduced pressure to thereby yield 8.4 g of the title compound (yield:78.4%).

¹H-NMR (300 MHz, CDCl₃): 8.01 (d, 2H, J=8.1 Hz), 7.68 (d, 2H, J=8.2 Hz),4.79 (s, 2H), 2.51 (s, 3H).

Example 6 Preparation of5-chloromethyl-4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole [Step C]

[4-Methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-yl]methanol (10.0 g,36.6 mmol) obtained from Example 2 was dissolved in anhydrousdichloromethane (250 ml) and then triphenylphosphine (TPP, 11.5 g, 44.0mmol, 1.2 eq.) and N-chlorosuccinimide (5.86 g, 44.0 mmol, 1.2 eq.) wereadded to the mixture sequentially at room temperature. After stirringfor 2 hours, the solvent was evaporated under reduced pressure.Subsequently, the remained triphenylphosphine oxide was precipitated byadding a mixed solvent of hexane and ethyl acetate (v/v=5/1), followedby filtration and evaporation under reduced pressure to thereby yield10.5 g of the title compound (yield: 98.5%).

Example 7 Preparation of2-Methyl-4-[({4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole-5-yl}methyl)sulfanyl]phenol[Step D]

4-Iodo-2-methylphenol (11.7 g, 50.0 mmol) was dissolved in anhydroustetrahydrofuran (400 ml) under nitrogen atmosphere and the temperaturewas maintained at 0° C. Isopropyl magnesium chloride (27.5 ml, 2M-ethersolution, 1.1 eq.) was added to the above mixture slowly and reacted for10 minutes. After cooling the reaction mixture to −78° C., tert-butyllithium (64.7 ml, 1.7M-heptane solution, 2.2 eq.) was added slowly andthe reaction mixture was reacted for another 20 minutes. A solution ofsulfur (1.60 g, 50 mmol, 1.0 eq.) in anhydrous THF (50 ml) was added tothe reaction mixture slowly and reacted until the temperature became 0°C. After 60 minutes, the temperature of the reaction mixture wasadjusted at 0° C. and5-chloromethyl-4-methyl-2-[(4-trifluoromethyl)phenyl]-thiazole offormula (VIII) (13.1 g, 45.0 mmol, 0.9 eq.) dissolved in anhydrous THF(40 ml) was added slowly. The reaction mixture was reacted for around 30minutes, followed by adding aqueous ammonium chloride solution (500 ml)to complete the reaction. The resultant organic layer was separated anddried over magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=3:1) to thereby yield 16.2 g of the title compound(yield: 91%)

¹H-NMR (300 MHz, CDCl₃): 7.96 (d, 1H, J=8.2 Hz), 7.64 (d, 2H, J=8.3 Hz),7.20 (d, 1H, J=1.8 Hz), 6.97 (dd, 1H, J=8.2, 2.2 Hz), 6.59 (d, 1H, J=8.2Hz) 5.52 (bs, 1H), 4.06 (s, 2H), 2.19 (s, 3H), 2.09 (s, 3H).

¹³C-NMR (75.5 MHz, CDCl₃): 164.1, 155.5, 151.7, 137.4, 136.8, 133.6,131.9 (q, J=33 Hz), 131.8, 131.6, 126.9, 126.4 (q, J=4 Hz), 125.9,123.8, 115.7, 33.2, 16.2, 14.8

Example 8 Preparation of2-Methyl-4-[({4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole-5-yl}methyl)sulfanyl]phenol[Step D]

4-Bromo-2-methylphenol (4.7 g, 25.0 mmol) was dissolved in anhydroustetrahydrofuran (150 ml) under nitrogen atmosphere and the temperaturewas maintained at 0° C. Isopropyl magnesium chloride (14.0 ml, 2M-ethersolution, 1.1 eq.) was added to the above mixture slowly and reacted for10 minutes. After cooling the reaction mixture to −78° C., tert-butyllithium (32.0 ml, 1.7M-heptane solution, 2.2 eq.) was added slowly andthe reaction mixture was reacted for another 20 minutes. A solution ofsulfur (800 mg, 25 mmol, 1.0 eq.) in anhydrous THF (30 ml) was added tothe reaction mixture slowly and reacted until the temperature became 0°C. After 40 minutes, the temperature of the reaction mixture wasadjusted at 0° C. and5-chloromethyl-4-methyl-2-[(4-trifluoromethyl)phenyl]-thiazole offormula (VIII) (6.55 mg, 23.0 mmol, 0.9 eq.) dissolved in anhydrous THF(25 ml) was slowly added. The reaction mixture was reacted for around 30minutes, followed by adding aqueous ammonium chloride solution (200 ml)to complete the reaction. The resultant organic layer was separated anddried over magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=3:1) to thereby yield 6.05 g of the title compound(yield: 68%)

Example 9 Preparation of2-Methyl-4-[({4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole-5-yl}methyl)sulfanyl]phenol[Step D]

4-Iodo-2-methylphenol (3.90 g, 16.7 mmol) was dissolved in anhydroustetrahydrofuran (120 ml) under nitrogen atmosphere and the temperaturewas maintained at 0° C. Isopropyl magnesium chloride (9.17 ml, 2M-ethersolution, 1.1 eq.) was added to the above mixture slowly and reacted for10 minutes. After cooling the reaction mixture to −78° C., tert-butyllithium (21.6 ml, 1.7M-heptane solution, 2.2 eq.) was added slowly andthe reaction mixture was reacted for another 20 minutes. A solution ofsulfur (534 mg, 17.0 mmol, 1.0 eq.) in anhydrous THF (15 ml) was addedto the reaction mixture slowly and reacted until the temperature became0° C. After 60 minutes, the temperature of the reaction mixture wasadjusted at 0° C. and5-bromomethyl-4-methyl-2-[(4-trifluoromethyl)phenyl]-thiazole of formula(VIII) (5.14 g, 15.0 mmol, 0.9 eq.) dissolved in anhydrous THF (12 ml)was added slowly. The reaction mixture was reacted for around 30minutes, followed by adding aqueous ammonium chloride solution (150 ml)to complete the reaction. The resultant organic layer was separated anddried over magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=3:1) to thereby yield 5.85 g of the title compound(yield: 87%)

Example 10 Preparation of ethyl{2-methyl-4-[({4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl}methyl)sulfanyl]phenoxy}acetate[Step E]

2-Methyl-4-{4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole-5-ylmethyl-sulfanyl}phenol (10.0 g, 25.0 mmol) obtained from Example 7 wasdissolved in acetone (300 ml) including 5% water and potassium carbonate(8.0 g, 58.0 mmol, 2.3 eq.) was added thereto at room temperature. Ethylbromoacetate (4.20 ml, 38.0 mmol, 1.5 eq.) was added for 4 hours whilestirring vigorously. After completion of reaction, the mixture wasextracted with brine and ethyl acetate, and the organic layer was driedover magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=5:1) to thereby yield 11.8 g of thetitle compound (yield: 98.5%).

¹H-NMR (300 MHz, CDCl₃): 7.97 (d, 2H, J=8.1 Hz), 7.66 (d, 2H, J=8.3 Hz),7.21 (d, 1H, J=1.7 Hz), 7.12 (dd, 1H, J=8.4, 2.3 Hz), 6.60 (d, 1H, J=8.4Hz), 4.62 (s, 2H), 4.24 (q, 2H, J=14.3, 7.1 Hz), 2.24 (s, 3H), 2.21 (s,3H), 1.28 (t, 3H, J=7.1 Hz).

¹³C-NMR (75.5 MHz, CDCl₃): 169.1, 163.0, 156.8, 136.5, 136.2, 132.5,132.1, 131.1 (q, J=32 Hz), 130.6, 128.8, 126.8, 126.2 (q, J=4 Hz),125.7, 122.4, 112.0, 66.0, 61.8, 32.9, 16.5, 15.2, 14.5

Example 11 Preparation of ethyl{2-methyl-4-[({4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl}methyl)sulfanyl]phenoxy}acetate[Step E]

2-Methyl-4-{4-methyl-2-[(4-trifluoromethyl)phenyl]thiazole-5-ylmethyl-sulfanyl}phenol (6.0 g, 15.0 mmol) obtained from Example 7 wasdissolved in dimethyl sulfoxide (100 ml) including 5% water, andpotassium carbonate (4.80 mg, 34.8 mmol, 1.5 eq.) was added thereto atroom temperature. Ethyl bromoacetate (2.52 ml, 22.8 mmol, 1.5 eq.) wasadded for 1 hours while stirring vigorously at 50° C. After completionof reaction, the mixture was extracted with brine and ethyl acetate, andthe organic layer was dried over magnesium sulfate. The solvent wasevaporated under reduced pressure, and The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=5:1) to therebyyield 7.02 g of the title compound (yield: 98%).

Example 12 Preparation of2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-yl}methyl)sulfanyl]phenoxy}aceticacid [Step F]

Ethyl {2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylsulfanyl]phenoxy}acetate obtained from Example 10 (5.0 g, 10.5 mmol) wasdissolved in ethanol (200 ml) and 3N sodium hydroxide solution (35.0 ml)was added thereto.

The reaction mixture was stirred for 30 minutes at room temperature.After completion of reaction, 2N HCl was added thereto for adjusting pHto be 2.0. Ethanol was evaporated by under reduced pressure and thereaction mixture was extracted with ethyl acetate and brine.Subsequently, the solvent was evaporated by under reduced pressure andthe residue was purified by LH-20 column chromatography to thereby yield4.71 g of the title compound (yield: 98.8%).

¹H-NMR (600 MHz, CD₃OD): 7.99 (d, 2H, J=8.2 Hz), 7.72 (d, 2H, J=8.2 Hz),7.17 (d, 1H, J=2.1 Hz), 7.14 (dd, 1H, J=8.4, 2.1 Hz), 6.72 (d, 1H, J=8.4Hz), 4.65 (s, 2H), 4.16 (s, 2H), 2.18 (s, 3H), 2.12 (s, 3H).

¹³C-NMR (150.9 MHz, CD₃OD): 172.7, 164.8, 158.2, 152.6, 138.2, 137.5,133.8, 133.3, 132.5 (q, J=33 Hz), 129.4, 127.8, 127.2 (q, J=4 Hz),126.2, 112.9, 66.3, 32.9, 16.4, 14.8

INDUSTRIAL APPLICABILITY

As described above, thiazole derivatives of formula (I) can be preparedin a high yield easily, according to the present invention.

1. A process for preparing a thiazole of formula (II)

comprising: (a) reacting a compound of formula (IX)

and a Grignard reagent to form a compound of formula (X)

(b) reacting the compound of formula (X) and a (C₁-C₁₀) alkyl to lithium to form an organic metal compound of formula (XI)

(c) reacting the organic metal compound of the formula (XI) and sulfur (S) to form a metal-sulfur compound of formula (XII)

and (d) reacting the metal-sulfur compound of formula (XII) and a thiazole a compound of formula (VIII)

to form the thiazole compound of formula (II); in which: R₁ represents a hydrogen atom, CF₃, or a halogen atom; R₂ represents a hydrogen atom, a (C₁-C₄) alkyl, a (C₁-C₄) alkyloxy, a (C₁-C₄) alkylthiooxy, a (C₁-C₄) alkylamine, a fluorine atom, or a chlorine atom; X₁ represents a halogen atom, a methane sulfonyloxy group, or a p-toluenesulfonyloxy group; X₂ represents a halogen atom; X₃ represents a halogen atom; m is an integer of 0 to 4; and n is an integer of 0 to
 5. 2. A process for preparing a thiazole compound of formula (VI)

comprising: (a) reacting a compound of formula (IX)

and a Grignard reagent to form a compound of formula (X)

(b) reacting the compound of formula (X) and a (C₁-C₁₀) alkyl lithium to form an organic metal compound of formula (XI)

(c) reacting the compound of the formula (XI) and sulfur (S) to form a metal-sulfur compound of formula (XII)

(d) reacting the compound of formula (XII) and a thiazole compound of formula (VIII)

to from a compound of formula (II)

(e) reacting the compound of formula (II) and an alkyl halogen acetate of formula (III)

to form the thiazole compound of formula (IV); in which: R₁ represents a hydrogen atom, CF₃, or a halogen atom; R₂ represents a hydrogen atom, a (C₁-C₄) alkyl, (C₁-C₄) alkyloxy, (C₁-C₄) alkylthiooxy, (C₁-C₄) alkylamine, a fluorine atom, or a chlorine atom; X₁ represents a halogen atom, a methane sulfonyloxy group or a p-toluenesulfonyloxy group; X₂ represents a halogen atom; X₃ represents a halogen atom; X represents a halogen atom; R₃ represents a methyl, ethyl, propyl, isopropyl, or a tert-butyl group as a protecting group of carboxyl acids; m is an integer of 0 to 4; and n is an integer of 0 to
 5. 